Lung-on-a-Chip Models of the Lung Parenchyma.

Since the publication of the first lung-on-a-chip in 2010, research has made tremendous progress in mimicking the cellular environment of healthy and diseased alveoli. As the first lung-on-a-chip products have recently reached the market, innovative solutions to even better mimic the alveolar barrier are paving the way for the next generation lung-on-chips. The original polymeric membranes made of PDMS are being replaced by hydrogel membranes made of proteins from the lung extracellular matrix, whose chemical and physical properties exceed those of the original membranes. Other aspects of the alveolar environment are replicated, such as the size of the alveoli, their three-dimensional structure, and their arrangement. By tuning the properties of this environment, the phenotype of alveolar cells can be tuned, and the functions of the air-blood barrier can be reproduced, allowing complex biological processes to be mimicked. Lung-on-a-chip technologies also provide the possibility of obtaining biological information that was not possible with conventional in vitro systems. Pulmonary edema leaking through a damaged alveolar barrier and barrier stiffening due to excessive accumulation of extracellular matrix proteins can now be reproduced. Provided that the challenges of this young technology are overcome, there is no doubt that many application areas will benefit greatly.

Enteric Coronavirus Infection and Treatment Modeled With an Immunocompetent Human Intestine-On-A-Chip.

Many patients infected with coronaviruses, such as SARS-CoV-2 and NL63 that use ACE2 receptors to infect cells, exhibit gastrointestinal symptoms and viral proteins are found in the human gastrointestinal tract, yet little is known about the inflammatory and pathological effects of coronavirus infection on the human intestine. Here, we used a human intestine-on-a-chip (Intestine Chip) microfluidic culture device lined by patient organoid-derived intestinal epithelium interfaced with human vascular endothelium to study host cellular and inflammatory responses to infection with NL63 coronavirus. These organoid-derived intestinal epithelial cells dramatically increased their ACE2 protein levels when cultured under flow in the presence of peristalsis-like mechanical deformations in the Intestine Chips compared to when cultured statically as organoids or in Transwell inserts. Infection of the intestinal epithelium with NL63 on-chip led to inflammation of the endothelium as demonstrated by loss of barrier function, increased cytokine production, and recruitment of circulating peripheral blood mononuclear cells (PBMCs). Treatment of NL63 infected chips with the approved protease inhibitor drug, nafamostat, inhibited viral entry and resulted in a reduction in both viral load and cytokine secretion, whereas remdesivir, one of the few drugs approved for COVID19 patients, was not found to be effective and it also was toxic to the endothelium. This model of intestinal infection was also used to test the effects of other drugs that have been proposed for potential repurposing against SARS-CoV-2. Taken together, these data suggest that the human Intestine Chip might be useful as a human preclinical model for studying coronavirus related pathology as well as for testing of potential anti-viral or anti-inflammatory therapeutics.